Drug resistance remains a major obstacle to the successful treatment of many cancers, and hence developing new strategies to prevent or overcome it is an important objective. This new R01 proposal is based on results of the previously funded exploratory R21 grant, under which we tested the efficacy of surface-modified biodegradable nanoparticles (NPs) to overcome drug resistance. Our data demonstrated that drug delivery with modified NPs can significantly overcome drug resistance. This was evident from a 13-fold enhancement in efficacy of doxorubicin and 25-fold of paclitaxel (PTX) in a resistant cell line and sustained tumor inhibition based on a single-dose intravenous administration of the PTX-loaded modified NPs vs. unmodified NPs or drug in Chremophore. The efficacy of our modified NPs in vivo could in part also be due to their better targeting and retention in tumor tissue than unmodified NPs. We speculate that the molecular structure of the surface-modifying agent at the NP interface influences the biophysical interactions of NPs with cell-membrane lipids, which then affect the cellular delivery of the encapsulated therapeutics and tumor targeting in vivo. We also speculate that co-delivery of a demethylating agent, decitabine in modified NPs would further reverse drug resistance. The overall objective of our study is to elucidate the molecular mechanisms of efficacy of the surface-modified NPs and to correlate the biophysical interactions of NPs with lipid membrane to their therapeutic efficacy. We hypothesize that an optimal combination of modified NPs can completely reverse drug resistance. The specific aims are: AIM 1: To study the effects of the molecular structure of a modifying agent at the NP interface on biophysical interactions of NPs with lipid membranes and correlate these interactions with drug efficacy in vitro, particularly in overcoming drug resistance; AIM 2: To study the biodistribution and tumor- specific delivery of modified NPs and determine their biocompatibility in vivo; and AIM 3: To demonstrate the efficacy of the optimized NPs in regressing drug-resistant tumors in a xenograft mouse model of breast cancer and to determine the mechanisms of efficacy. We propose an innovative approach to overcoming drug resistance in cancer therapy, the successful outcome of which will have significant clinical benefits, particularly in treating cancers that are refractory to normal drug therapy. Furthermore, an effective therapy with our modified NPs might prevent the cancer from developing drug resistance.